With the rise of antibiotic resistance, the reservoir of effective drugs available for treatment of various bacterial infections has become dangerously low. For decades, chemists utilized a tool known as semisynthesis in order to combat the threat of antibiotic resistance. A semisynthetic strategy relies heavily on the isolation and fermentation of complex antibiotics from nature that are subsequently modified through chemical synthesis. Although semisynthesis has proven to be an extremely useful tool in antibiotic discovery, it is inherently limited. That is, semisynthetic methods are structurally constrained, as starting substrates are extremely complex with many competing functionalities that make certain chemical transformations difficult or nearly impossible. In an attempt to gain control over the impending crisis of antibiotic resistance, a fully-synthetic platform towards macrolide antibiotics was adopted. Drawing lessons from recent crystallographic studies that elucidated the interactions of antibiotics bound to the bacterial ribosome and molecular modeling, new chemical modifications of macrolide antibiotics can be rationalized to improve their on-target binding affinity. Lowest energy conformers of target macrolides were calculated and modeled using molecular mechanics and density functional theory (DFT). Here, a computer-guided, structure-based approach to the design and total synthesis of new macrolide antibiotics is presented. Moreover, a series of ketolide antibiotics bearing a carbazate-linker and various aryl moieties was synthesized and evaluated for biological activity against a panel of gram-positive and gram-negative bacteria. Of these newly synthesized macrolides, several have demonstrated promising activity against macrolide-resistant bacterial strains.

Design and synthesis of novel macrolide antibiotics as tools against resistant bacteria

255th National Meeting (2018)

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